Acyltransferases comprise a large family of enzymes that regulate biological processes by catalyzing the transfer of acyl groups to a wide variety of biological and chemical substrates, including proteins, lipids, and nucleic acids (E. C. Webb ed., Enzyme Nomenclature, pp. 178–201, ©1992 Academic Press, Inc. San Diego, Calif.).
The biosynthesis of complex lipids involves specific acylation reactions catalyzed by acyltransferases. Lipids are ubiquitous biomolecules that play a critical role in cell structure and metabolism. For example, triacylglycerols are the principal storage form of energy; cholesterol is a component of cell membranes and a precursor of steroid hormones and bile acids; glycolipids and phospholipids are major components of biological membranes; and arachidonate is a precursor of pleiotropic intercellular mediators including the prostaglandins, prostacyclins, thromboxanes, and leukotrienes.
The de novo biosynthesis of glycerophospholipids, which include phospholipids and triacylglycerol, involves the esterification of glycerol-3-phosphate with a fatty acyl-CoA in the sn-1 position by glycerol-3-phosphate acyltransferase (GPAT) to form 1-acylglycerol-3-phosphate (lysophosphatidic acid). Lysophosphatidic acid is then esterified in the sn-2 position with a fatty acyl-CoA by 1-acylglycerol-3-phosphate acyltransferase (AGPAT) to form 1,2-diacylglycerol-3-phosphate (phosphatidic acid). Ultimately, phosphatidic acid can be converted to phosphatidylinositol, phosphatidylglycerol and cardiolipin via a CDP-diacylglycerol intermediate. Alternatively, phosphatidic acid can be dephosphorylated to form diacylglycerol, which is used for the synthesis of triacylglycerol, as well as phospholipids including phosphatidylcholine and phosphatidlyethanolamine.
Glycerol-3-phosphate acyltransferase (GPAT) is the first committed, and presumably rate-limiting, step in glycerophospholipid biosynthesis (Wilkison, WO and Bell, RM (1997) Biochim. Biophys. Acta 1348:3–9; Dircks, L and Sul H S (1999) Prog. Lipid Res. 38:461–479). Two isoforms of this enzyme have been detected in mammals, a mitochondrial and an endoplasmic reticulum isoform, which can be distinguished by differential sensitivity to N-ethylmaleimide (NEM). Treatment of mitochondrial GPAT with arginine-modifying agents, phenylglyoxal and cyclohexanedione, incativated the enzyme (Dircks, L et al. (1999) J. Biol. Chem. 274:34728–34). The expression of mitochondrial GPAT is under nutritional and hormonal control in lipogenic tissues such as liver and adipose tissue, as is regulated during adipocyte differentiation (Yet, S-F et al. (1993) Biochemistry 32:9486–91; Yet, S-F et al. (1995) Biochemistry 34:7303–10).
Acyltransferases also play an important role in the fatty acid remodeling of phospholipids, as well as the metabolism of bioactive lipids (Yamashita, A et al. (1997) J. Biochem. 122:1–16). Fatty acid remodeling is central to physiological processes including the regulation of the physiochemical properties of membranes, e.g., membrane fluidity, and the regulation of the distribution and accumulation of biologically active fatty acids, e.g., arachidonic acid. The phospholipid bilayer of biological membranes serves as a permeability barrier to compartmentalize specialized functions in the cell, and mediates cellular functions such as ion and metabolite transport, electron transport, and signal transduction. Moreover, fatty acylation of cellular proteins may have important functional consequences such as the modulation of subcellular localization (e.g., membrane targeting) and signaling. Therefore, acyltransferases contribute to the ability of the cell to grow and differentiate, to proliferate, to adhere and move, and to interact and communicate with other cells.